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Supplemental Table 3. Pain Group Evidence Summaries and Evidence to Decision Tables

Question: Adjunctive nefopam compared to no adjunctive nefopam for ICU pain management (5.2)

Quality assessment

№ of patients

Effect

Quality

Importance

№ of studies

Study design

Risk of bias

Inconsistency

Indirectness

Imprecision

Other considerations

adjunctive nefopam

no adjunctive nefopam

Relative (95% CI)

Absolute (95% CI)

VAS Score with movement

1

randomised trials

serious a

not serious

serious b

serious c

none

Overall no difference in Pain assessment with or without nefopam: at rest and during movement at 12, 24, 36, 48 and 72 h after surgery using a visual analogue scale (VAS) Pain with movement at 48h was the only time point for which the difference was statistically significant. All others were non-significant.

⨁◯◯◯ VERY LOW

CRITICAL

CI: Confidence interval; MD: Mean difference

Explanations

a. Randomization method not described, no intention to treat with 24/300 loss to follow-up, blinding described

b. Only included CVICU patients in this study, however analgesic efficacy may be broadly applicable to all ICU patients

c. Confidence Intervals do not cross z ero (no effect) - however small sample siz e hard to draw conclusion on nefopam effects

Question

Should adjunctive nefopam vs. no adjunctive nefopam be used for ICU pain management (5.2)?

Population:

ICU pain management (5.2)

Background:

Intervention:

adjunctive nefopam

Comparison:

no adjunctive nefopam

Main outcomes:

VAS Score with movement;

Setting:

Perspective:

Judgement

Research evidence

Additional considerations

Problem

Is the problem a priority?

○ No ○ Probably no ○ Probably yes ● Yes

○ Varies ○ Don't know

It is top priority to investigate the effectiveness/side effects of Adjunctive Non opioid analgesics to opioids compared to opioids alone in order to decrease opioids related side effects that are especially at risk in ICU patients:

- respiratory depression

- neurological impairment (decreased vigilance, delirium)

- ileus, nausea vomiting, etc...

Kim et al. 2014 [1]

n=276 patients scheduled to undergo cardiac surgery were randomly assigned between three

PCA groups (92 patients per group): nefopam, fentanyl or nefopam + fentanyl.

Each drug was given continuously + in PCA mode.

NB (1): For Question 5.2, we only take into consideration nefopam+fentanyl group versus fentanyl group.

Pain assessment:

at rest and during movement

at 12, 24, 36, 48 and 72 h after surgery using a visual analogue scale (VAS)

NB (2): The evidence table reported only pain at H48 which was the only time point for which the difference was statistically significant.

Doses:

nefopam group:

nefopam 4 mg/h

bolus: nefopam 2 mg (lock out ime = 15 min)

fentanyl group:

fentanyl 20 µg/h

bolus: fentanyl 10 µg (lock out ime = 15 min)

nefopam+fentanyl group:

nefopam 1.86 mg/h + fentanyl 9.4 µg/h

bolus: nefopam 0.93 mg + fentanyl 4.7 µg

(lock out ime = 15 min in every group)

Desirable Effects

How substantial are the desirable anticipated effects?

○ Trivial ● Small ○ Moderate ○ Large

○ Varies ○ Don't know

This study has a "Non inferiority design"

According to the study design, there was no inferiority of nefopam (adjunctive or not) compared to fentanyl (VAS non significant at H24 at rest and during movement).

Note that fentanyl dose changes according to the group from 0 (no fentanyl, nefopam only) to 9.4 µg/h (nefopam+fentanyl group) to 20 µg/h (fentanyl only)

VAS also non significant at H12, 24, 36, 48, 72 at rest, as well as during movement at H12, 24, 36, 72.

The VAS difference between group is only significant during movement at H48:

MD 0.34 higher (0.01 higher to 0.67 higher)

i.e. VAS higher in nefopam+fentanyl group compared to fentanyl alone group

"large" desirable anticipated effects because nefopam did as well as fentanyl, a good point for nefopam if we would like to spare opioids.

Undesirable Effects

How substantial are the undesirable anticipated effects?

○ Large ○ Moderate ● Small ○ Trivial

○ Varies ○ Don't know

"small" undesirable anticipated effects

beucause on the contrary, nausea was less frequent in the nefopam+fentanyl group (13%) compared to the fentanyl group (27%), p<0.01 taking into account the three groups (nefopam, nefopam+fentanyl, fentanyl).

No significant difference between groups for: tachycardia, sweating, sedation, dyspnoa, prutirus, vomiting.

(All adverse events were reported during the first 48 hours).

No post-hoc tests comparing groups in pairs.

Certainty of evidence

What is the overall certainty of the evidence of effects?

○ Very low ● Low ○ Moderate ○ High

○ No included studies

n=92 patients per group is a small group for John Centofanti.

There was an important ROB:

Randomization method not described, no intention to treat with 24/300 loss to follow-up

Reasons for non completion of the study:

-duration of intubation > or = 48h: n=11 (it is not precised the timing of begining of the PCA with continuous mode, only that ot was "initiated postoperatively")

-repeat surgery within 72h: n=5

-reintubation in ICU: n=4

-malfunctionning PCA device: n=4

"low" certainty of the evidence of effects because of:

- a moderate to important size (almost 100!)

- a double blinded design

but

- only one study

- with an important ROB

Values

Is there important uncertainty about or variability in how much people value the main outcomes?

○ Important uncertainty or variability ○ Possibly important uncertainty or variability ○ Probably no important uncertainty or variability ● No important uncertainty or variability ○ No known undesirable outcomes

Except for nausea, other classical opioid related side effects were not decreased nor investigated (respiratory rate, ileus, delirium...).

"Possibly" important uncertainty or variability

Balance of effects

Does the balance between desirable and undesirable effects favor the intervention or the comparison?

○ Favors the comparison ○ Probably favors the comparison ○ Does not favor either the intervention or the comparison ● Probably favors the intervention ○ Favors the intervention

○ Varies ○ Don't know

Globally no statistical difference (or small difference) of pain intensity but less nausea in nefopam+fentanyl group (intervention) compared to fentanyl alone group (comparison).

Also, there is at least a 50% reduction in fentanyl dose in the nefopam+fentanyl group (see dosing above, no difference in PCA volume between groups).

"the balance between desirable and undesirable effects favors the intervention"

Resources required

How large are the resource requirements (costs)?

○ Large costs ● Moderate costs ○ Negligible costs and savings ○ Moderate savings ○ Large savings

○ Varies ○ Don't know

Nefopam costs are very small in France (20 mg = $0.39; between $1.56 and $2.34 per day usually, 2016 prices in Montpellier Hospitals) but must probably depend on the country.

Not available in the US and Canada.

Countries where nefopam was available in 2010:

BAHRAIN - TABLETS ONLY

BELGIUM

CHILE

DOMINICAN REPUBLIC

EGYPT

EQUATOR - TABLETS ONLY

FRANCE

GERMANY - TABLETS ONLY

HAITI

HONG KONG - TABLETS ONLY

IRLAND

LUXEMBOURG

MALAISIA

MALTA

MAURITIUS

MEXICO

NEW ZEALAND - TABLETS ONLY

OMAN

PAKISTAN

PANANA

QATAR

SALVADOR

SINGAPOUR - TABLETS ONLY

SWITZERLAND

THE BARBADOS - TABLETS ONLY

UNITED ARAB EMIRATES

UNITED KINGDOM

"moderate costs"

because this study used a PCA device but not the drug costs

Certainty of evidence of required resources

What is the certainty of the evidence of resource requirements (costs)?

○ Very low ● Low ○ Moderate ○ High

Cost and availability not known in every country

See above.

Cost effectiveness

Does the cost-effectiveness of the intervention favor the intervention or the comparison?

○ Favors the comparison ○ Probably favors the comparison ○ Does not favor either the intervention or the comparison ● Probably favors the intervention ○ Favors the intervention ○ Varies ○ No included studies

PCA was used in the two groups (no increased costs related to the PCA that was used in the two groups).

Regarding the drug: nefopam might be less or more expensive than fentanyl (depends on local costs).

Also to take into consideration, if nausea is less frequent, antiemetic drugs should be less required for rescue (this should decrease the averall cost of the drugs).

NB: ramosetron was systematically given in both groups to reduce nausea.

cost-effectiveness "probably" favors the intervention

Equity

What would be the impact on he